Disorders of hepatic gluconeogenesis and lipogenesis may lead to metabolic problems such as diabetes, dyslipidemia, and fatty liver. Our long-term goal is to investigate the mechanisms by which p38 regulates hepatic gluconeogenesis and lipogenesis, and provide new targets for the prevention and treatment of metabolic disorders such as diabetes and dyslipidemia. The specific hypothesis is that activation of p38 stimulates gluconeogenesis, while simultaneously inhibiting lipogenesis;the stimulatory role of p38 is accomplished by promoting the function of peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 alpha (PGC-1 alpha), while the inhibitory role of p38 is mediated by suppressing expression of the PPARgamma coactivator-1 beta (PGC-1 beta) gene. This hypothesis is based on our observations that 1) p38 is activated in liver by fasting and in isolated hepatocytes by glucagon;2) p38 stimulates expression of the PGC-1 alpha gene, but inhibits expression of the PGC-1 beta gene;3) Inhibition of p38 reduces expression of key gluconeogenic genes, while increasing expression of key lipogenic genes;and 4) The blockade of p38 leads to decreased levels of fasting plasma glucose and increased lipid levels in blood and liver. Four specific aims are proposed to test the hypothesis. Aim 1: To characterize the key components by which p38 regulates transcription of the PGC-1 alpha gene in hepatic gluconeogenesis. Aim 2: To determine how p38 inhibits transcription of the PGC-1 beta gene in hepatic lipogenesis. Aim 3: To delineate the transcriptional components required for p38 regulation of the central lipogenic gene, sterol regulatory element binding protein-1c (SREBP-1c). Aim 4: To test the hypothesis that the blockade of p38 can reduce blood glucose levels in diabetic animals. Methods: Hepa-1c1c7 and FAO hepatoma cell lines, primary hepatocytes, and normal and diabetic C57BL/6 mouse models will be used in this study. A variety of molecular approaches will also be used. Significance: This study will provide new insight into mechanisms by which hepatic gluconeogenesis and lipogenesis are regulated. Completion of this study may provide new targets for the prevention and treatment of diabetes and lipid disorders.